Dataset Information

Role of low-density lipoprotein receptor rs5925 (1959C>T) gene polymorphism in pathogenesis of dyslipidemia among Egyptian lupus nephritis patients.

ABSTRACT:

Objectives

This study aims to investigate the prevalence of low-density lipoprotein receptor (LDL-R) rs5925 genetic variants and to evaluate their relationship with plasma lipid and kidney functions in lupus nephritis patients.

Patients and methods

Between September 2020 and June 2021, a total of 100 lupus nephritis patients (8 males, 92 females; mean age: 31.1±1.1 years; range, 20 to 67 years) and a total of 100 age- and sex-matched healthy volunteers (10 males, 90 females; mean age: 35.8±2.8 years; range, 21 to 65 years) were included. The gene polymorphism rs5925 (LDLR) was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Lipid profile and kidney functions were measured.

Results

Regarding rs5925 (LDLR), C allele was significantly higher among lupus nephritis patients (60%) compared to the control group (45%). While T allele was significantly lower in lupus nephritis patients (40%), compared to the control group (p=0.003). The plasma level of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) were significantly lower in lupus nephritis patients with TT and CT genotypes, compared to those with CC genotype. Moreover, atherogenic index of plasma (AIP) and LDL-C/high-density lipoprotein cholesterol (HDL-C) ratio were significantly lower in patients with TT genotype, compared to the patients with CC genotype. There was a strong and clear association between patients with renal biopsies grades III & IV & V and LDLR C allele (p=0.01, p=0.003, and p=0.004, respectively).

Conclusion

C allele is the significantly prevailed LDLR C1959T variant among lupus nephritis patients. Moreover, LDL-R genetic variant may be one of the non-immunological mechanisms implicated in the disturbed lipid profile among lupus nephritis patients. Profound dyslipidemia may partly underscore the deterioration of kidney function among lupus nephritis patients.

SUBMITTER: Alsabbagh YA

PROVIDER: S-EPMC9985366 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Role of low-density lipoprotein receptor rs5925 (1959C>T) gene polymorphism in pathogenesis of dyslipidemia among Egyptian lupus nephritis patients.

Alsabbagh Yumn A YA Ahmed Saher A SA Salama Heba E HE Abd-Elmawla Mai A MA Elgendy Hala L HL

Archives of rheumatology 20220506 4

<h4>Objectives</h4>This study aims to investigate the prevalence of low-density lipoprotein receptor (LDL-R) rs5925 genetic variants and to evaluate their relationship with plasma lipid and kidney functions in lupus nephritis patients.<h4>Patients and methods</h4>Between September 2020 and June 2021, a total of 100 lupus nephritis patients (8 males, 92 females; mean age: 31.1±1.1 years; range, 20 to 67 years) and a total of 100 age- and sex-matched healthy volunteers (10 males, 90 females; mean ...[more]

PMID: 36879570

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Project description:Background: The low-density lipoprotein receptor (LDLR) in the liver plays a crucial role in clearing low-density lipoprotein cholesterol (LDL-C) from the bloodstream. This process takes place mainly in the liver. Under atherogenic conditions, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), secreted by the liver, binds to LDLR on hepatocytes, preventing its recycling and enhancing its lysosomal degradation. This process reduces LDL-C clearance, promoting hypercholesterolemia. Epsins, a family of ubiquitin-binding endocytic adaptors, are key regulators of atherogenesis in lesional cells, including endothelial cells and macrophages. Given epsins' canonical role in regulating endocytosis of cell-surface receptors, we aimed to determine whether and how liver epsins contribute to PCSK9-mediated LDLR endocytosis and degradation, thereby impairing LDL-C clearance and accelerating atherosclerosis. Methods: Liver-specific epsin knockout (Liver-DKO) atherosclerotic models were generated in ApoE-/- and PCSK9-AAV8-induced atheroprone mice fed on a Western diet. We utilized single-cell RNA sequencing, along with molecular, cellular, and biochemical analyses, to investigate the physiological role of liver epsins in PCSK9-mediated LDLR degradation. Additionally, we explored the therapeutic potential of nanoparticle-encapsulated siRNAs targeting epsins 1 and 2 in ApoE-/- mice with established atherosclerosis. Results: Western diet (WD)-induced atherosclerosis was significantly attenuated in ApoE-/-/Liver-DKO mice compared with ApoE-/- controls, as well as in PCSK9-AAV8-induced Liver-DKO mice compared with PCSK9-AAV8-induced wild-type (WT) mice, accompanied by reductions in blood cholesterol and triglyceride levels. Mechanistically, single-cell RNA sequencing of hepatocytes and aortas isolated from atherosclerotic ApoE-/- and ApoE-/-/Liver-DKO mice revealed epsin-deficient Ldlrhi hepatocytes with diminished lipogenic potential. Notably, pathway analysis of hepatocytes revealed increased LDL particle clearance and enhanced LDLR-cholesterol interactions under WD treatment in ApoE-/-/Liver-DKO mice compared with ApoE-/- controls, which correlated with decreased plasma LDL-C levels. Furthermore, pathway analysis of the aortas showed attenuated inflammation and endothelial activation, coupled with reduced lipid uptake, and enhanced cholesterol efflux under WD treatment in ApoE-/-/Liver-DKO mice compared with ApoE-/- controls. Moreover, the absence of liver epsins led to an upregulation of LDLR protein expression in hepatocytes. We further demonstrated that epsins bind LDLR via the ubiquitin-interacting motif (UIM), enabling PCSK9-mediated LDLR degradation. Depleting epsins abolished this degradation, thereby preventing atheroma progression. Lastly, targeting liver epsins with nanoparticle-encapsulated epsins siRNAs effectively ameliorates dyslipidemia and inhibits atherosclerosis progression. These results are consistent with findings showing increased expression of epsin1 and epsin2 in patients with atherosclerotic cardiovascular disease. Conclusions: Liver epsins drive atherogenesis by promoting PCSK9-mediated LDLR degradation, thereby elevating circulating LDL-C levels and heightening lesional inflammation. As such, targeting epsins in the liver represents a promising therapeutic strategy to mitigate atherosclerosis by preserving LDLR and enhancing LDL-C clearance.

Dataset Information

Role of low-density lipoprotein receptor rs5925 (1959C>T) gene polymorphism in pathogenesis of dyslipidemia among Egyptian lupus nephritis patients.

Objectives

Patients and methods

Results

Conclusion

Publications

Role of low-density lipoprotein receptor rs5925 (1959C>T) gene polymorphism in pathogenesis of dyslipidemia among Egyptian lupus nephritis patients.

Similar Datasets

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